Worldwide, up to 2 million infants die each year before the age of 5. Disease susceptibility and mortality are highest in the first 6 months of age. However, our knowledge of immune development after birth and how it relates to disease susceptibility, infant mortality, and childhood vaccine efficacy is still limited. The majority of immunological data related to immune development in infants are based on the comparison of cord blood to adult blood. Few longitudinal studies have been performed, and thus the kinetics of immune maturation is largely unknown. Sample access, sample volumes and the frequencies at which sample collection is possible present obvious hurdles, and as a result many previous studies were limited to low sample numbers (<50 infants). In the proposed studies here, we will have access to longitudinal samples from 560 infants. A unique aspect will be the inclusion of healthy pre-term babies. Thus, we will be able to directly compare immune development between pre-term and full-term infants. These studies will provide new insights into how gestational age and immune maturation affect disease susceptibility, infant mortality and childhood vaccine efficacy. The long-term goal of our studies is to delineate distinct immune mechanisms that differ between infants and adults. There is a significant lack of studies defining the molecular mechanisms responsible for reduced immunologic responsiveness in infants. Few studies have attempted to define age-related differences in signaling pathways, gene expression or regulation that may account for the observed functional differences between infant and adult immune cell populations. The specific objective of the studies proposed here is to characterize the immune maturation of myeloid dendritic cells (mDC) and CD4+T cells from birth to 1 year of age and to define the molecular mechanisms involved in the functional development of these two cell populations. Myeloid DC and CD4+T cells play central roles in innate and adaptive immunity, respectively. To study the kinetics of immune maturation after birth, to define molecular mechanisms associated with immune development, and to determine potential differences in immune development in pre-and full-term infants, we will pursue 3 Specific Aims. In Aims 1 and 2, we will characterize mDC and CD4+T cell maturation, respectively, in pre-and full-term infants from birth to 1 year of age. In the last aim, we will tet how potential differences in immune development between pre- and full-term infants are reflected in vaccine-induced immunity. This knowledge should be of great clinical relevance, and demonstrates the translational nature of the proposed studies. The study is a collaborative effort by basic researchers (Dr. Abel and lab) and neonatologists and pediatricians led by Dr. W. Price. PUBLIC HEALTH RELEVANCE: Infants during their first year of life represent one of the most vulnerable populations. To reduce childhood morbidity and mortality, we need a better understanding of immune development. Thus, we need to define distinct immune mechanisms that differ between infants and adults, determine the kinetics of immune maturation after birth, and identify which factors influence immune development. Towards this goal, the proposed studies will examine molecular mechanisms of immune development and determine how immune maturation differs between pre- and full-term infants, and whether such differences affect vaccine-induced immunity.